New research suggests that accurately predicting ejection fraction (EF) trajectory phenotypes can inform the personalization of prognosis and treatment for children with acute myeloid leukemia (AML).
Study group-based trajectory methods identified distinct EF trajectory phenotypes with differential event-free survival and overall survival for each group.
“Predictive models focused on trajectory-defined phenotypes can elucidate the genomic and environmental determinants of anthracycline-associated cardiotoxicity more effectively than investigations of incident occurrence alone,” the study author wrote. Kelly D. Getz, PhD, MPH, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania.
The findings were presented at the 2022 American Society of Hematology (ASH) Meeting in New Orleans.
Pediatric patients treated for AML receive high doses of anthracyclines which can cause significant short- and long-term morbidity and mortality. As Getz and colleagues note, knowledge of its natural history and its impact on treatment outcomes is essential for care.
Previous evaluation of cardiotoxicity in pediatric AML has focused on the occurrence of incident declines below a left ventricular (LV) EF threshold. By expanding to longitudinal EF trajectories, it may provide a mechanism to better understand high-risk phenotypes, inform prognosis, and identify critical windows for intervention.
Thus, between June 2011 and September 2018, the AAML1031 trial recruited patients aged 30 and under with de novo AML. Treatment required echocardiographic evaluation before each treatment cycle, at the end of the treatment protocol, and annually during off-protocol follow-up, where the resulting EF measurements were collected.
A group-based trajectory model was used to identify latent subgroups with distinct patterns of longitudinal change in EF from baseline. Analyzes were limited to patients with a baseline EF measurement and at least two additional EF measurements during the study period. Multivariable adjusted Cox regression compared event-free survival and overall survival for the identified EF trajectory groups.
A total of 1063 patients contributed a total of 7284 EF measurements (median, 6; IQR, 5 – 11 per person). In the final model, three distinct latent groups were identified including a linear trajectory and two cubic trajectories.
The data show that 47% of the patients were classified in group 1 (preserved EF), 47% in group 2 (moderate persistent reduction in EF) and 6% in group 3 (dramatic decline in EF with incomplete recovery ). The mean posterior probabilities reported were 0.87, 0.86, and 0.90 for groups 1 to 3, respectively.
In addition, the proportion of infants decreased from group 1 to group 3 (G1: 23%, G2: 16%, G3: 11%; P <.01). The third group had a higher proportion of non-Hispanic black patients (G1: 12%, G2: 11%, G3: 24%; P = 0.02) and a slightly higher proportion of women (G1: 49%, G2: 46%, G3: 58%; P = 0.17), compared to groups 1 and 2.
The use of dexrazocane was less likely in groups 2 and 3 compared to group 1 (G1: 17%, G2: 7%, G3: 7%; P <.001). Investigators found no significant differences in insurance, weight, risk classification, or treatment arm distributions.
Event-free survival (G1: 48%, G2: 47%; P = 0.72) and overall survival (G1: 68%, G2: 64%; P = 0.22) were comparable between groups 1 and 2. At the same time, event-free survival (G1: 48%, G3: 30%; P = 0.003) and overall survival (G1: 68%, G3: 38%; P <.001) have been significantly reduced.
In analyzes restricted to patients completing AAML1031 therapy, the team of investigators identified comparable trajectories, but with higher mean posterior probabilities (G1: 0.89, G2: 0.90 and G3: 0.94) . It was noted that these patients had a more complete capture of LVEF measurements in the study database.
“Work is underway to identify supportive care practices that may alter distinct EF trajectory phenotypes,” Getz wrote.
The study, “Distinct Latent Trajectory Phenotype of Left Ventricular Function Associated with Differential Survival Among Children Treated for Acute Myeloid Leukemia: A Report from the Children’s Oncology Group,” was presented at CASH 2022.
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